We recently discovered that RGS14 is a novel mediator of hippocampal-based learning/memory. We find that RGS14 is expressed predominantly in brain, specifically within dendrites/neurites of hippocampal neurons important for learning/memory (i.e. pyramidal cells of the CA1/CA2 region). Our novel mice lacking the RGS14 gene/protein (RGS14-KO) exhibit a marked enhancement of spatial learning/memory and novel-object recognition and of long-term potentiation (LTP) of postsynaptic neurotransmission in CA1 neurons. These findings strongly suggest that RGS14 regulates signaling events critically important for hippocampal-based learning/memory. However, the molecular and cellular actions of RGS14 in hippocampal neurons remain poorly defined. We find that RGS14 binds Ric8A, an unconventional guanine- nucleotide exchange factor activator for G1i, and also to inactive Gi11/3-GDP, active H-Ras and Rap2 and their effectors the Raf kinases. In cells, RGS14 co-localizes with its binding partners at the plasma membrane to inhibit stimulated Ras/Raf/Erk signaling. When complexed with its partners in cells, RGS14 is phosphorylated at unknown site(s) with unknown functional consequences. Of note, RGS14 partners H-Ras, Rap2, Gi and linked Erk pathways regulate synaptic plasticity associated with learning/memory in hippocampal neurons including neurite outgrowth, dendritic remodeling, and trafficking of glutamate receptors. My working hypothesis is that RGS14 is a tightly regulated scaffolding protein that integrates unconventional Gi and H-Ras/Raf/MAPkinase signaling events important for synaptic plasticity involved with learning, memory and cognition in the hippocampus. Our Specific Aims will be to: Aim 1. Determine the protein/protein interactions and molecular mechanisms by which RGS14 integrates unconventional Ric8A/Gi1 and H-Ras/Rap2/Raf kinase signaling. Aim 2: Determine sites on RGS14 that are phosphorylated when complexed with Gi11/3, H- Ras or Rap2 in cells, the involved kinases, and how phosphorylation impacts RGS14 signaling. Aim 3: Determine roles for RGS14 in regulating molecular and physical markers of H- Ras/Raf/MAPkinase-directed synaptic plasticity in hippocampal neurons. Aim 4: Determine roles for RGS14 in regulating postsynaptic neurotransmission and linked behaviors that result from H-Ras/Raf/Erk-directed synaptic plasticity in the hippocampus Rap/MAPkinase signaling events and the morphology of primary hippocampal neurons. Impact: These studies will provide key insight about RGS14 as a novel regulator and integrator of neurotransmitter signaling events that modulate neuronal plasticity, learning and memory.